Project Summary Anorexia nervosa (AN) and its associated complications impose a huge burden to our society. However, the cellular and circuits mechanisms underlying this eating disorder are largely unknown, and effective treatments are still lacking. At its core, anorexia nervosa is an emotional disorder characterized by persistent and severe self-restriction of food intake and commonly co-occurring with anxiety. Most work has focused on hypothalamic homeostatic control of food intake. An important but poorly understood element is the emotional aspect of food intake. To further our understandings of the neural mechanisms of anorexia nervosa and develop new clinical therapeutic strategies to treat this eating disorder, it thus is critical to decipher the neural circuits underlying this disorder and determine whether the neural circuits for anorexia and anxiety are distinct or overlapping. Our long-term goal is to enable the development of novel targets to correct or reverse eating disorders, such as anorexia nervosa. Our overall objective for this application is to dissect the neural circuits that mediate the ventral hippocampal anorexigenic effects on food intake and their anxiogenic effects. Our central hypothesis is that the ventral hippocampus suppresses food intake by projecting glutamatergic inputs to the lateral septum (LS) to activate GABAergic neurons in the LS, which subsequently inactivates GABAergic neurons in the lateral hypothalamus (LH). Our hypothesis has been formulated on the basis of our recent study and our preliminary data which will be detailed in the Approach section. The work of Jennings et al. (2014) and Wu et al. (2015) provides additional support for this hypothesis. The rational for the proposed research is that, once the neural circuits underlying the ventral hippocampus (vHPC)-based anorexia nervosa are identified, it may be feasible to pharmacologically manipulate them to treat this disorder, and potentially other eating disorders. To accomplish our goals, we have assembled a research team that combines expertise of feeding and emotions. To test our central hypothesis and thereby accomplish our overall objective, we will carry out three Specific Aims: (1) Identify and characterize LS neuron populations mediating vHPC suppression of feeding; (2) Identify LS neuron populations that relay the vHPC appetitive suppressive information to LH; (3) Determine the anxiogenic effects of the neural circuits mediating the vHPC-based anorexia. Collectively, the vHPC-based anorexia and anxiety and the involved neural circuits will be studied using state-of-the-art methodologies that include optogenetic-assisted circuit mapping, single-cell gene analysis, feeding and emotional behavioral tests, chemogenetic-and optogenetic neural manipulations. Results using these cutting-edge methods will give us unprecedented access to understanding the cellular and circuit mechanisms of the vHPC-based anorexia nervosa. The proposed research represents a new and substantial departure from other studies in that it shifts the focus to understanding emotional aspects of food intake and developing new therapeutic targets for AN.